title: Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency.
abstract: Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone that acts primarily on the kidney and parathyroid. With declining kidney function there is an increase in circulating FGF23 levels, which is associated with vascular calcification and mortality in chronic kidney disease. Whether FGF23 exerts direct effects on vasculature is unclear. We evaluated the expression of Klotho and FGF receptors in rat aortic rings and rat aorta vascular smooth muscle cells maintained in culture by reverse transcription-PCR, western blotting, and immunostaining. Signaling pathways underlying FGF23 effects were assessed by western blotting, and effects of FGF23 on osteogenic markers and phosphate transporters were assessed by real-time reverse transcription-PCR. We detected Klotho and FGFR1 in total aorta but not in vascular smooth muscle cells. FGF23 augmented phosphate-induced vascular calcification in the aortic rings from uremic rats and dose dependently increased ERK1/2 phosphorylation in Klotho-overexpressing but not naive vascular smooth muscle cells. FGF23-induced ERK1/2 phosphorylation was inhibited by SU5402 (FGFR1 inhibitor) and U0126 (MEK inhibitor). FGF23 enhanced phosphate-induced calcification in Klotho-overexpressing vascular smooth muscle cells and increased osteoblastic marker expression, which was inhibited by U0126. In contrast, phosphate transporter expression was not affected by phosphate or FGF23. Thus, FGF23 enhances phosphate-induced vascular calcification by promoting osteoblastic differentiation involving the ERK1/2 pathway.
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Jimbo
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Kawakami-Mori
authors.affiliation: Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (RCAST), University of Tokyo, Meguro-ku, Tokyo, Japan.
authors.forename: Shengyu
authors.initials: S
authors.lastname: Mu
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Daigoro
authors.initials: D
authors.lastname: Hirohama
authors.affiliation: Department of Cardiology and Angiology, Frankenwaldklinik Kronach, Bavaria,Germany.
authors.forename: Bohumil
authors.initials: B
authors.lastname: Majtan
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Department of Clinical Laboratory, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Fukumoto
authors.affiliation: Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (RCAST), University of Tokyo, Meguro-ku, Tokyo, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Department of Clinical Laboratory, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism / Q000633:toxicity*; D005966:Glucuronidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010710:Phosphates / Q000633:toxicity*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000633:toxicity; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D061205:Vascular Calcification / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology
chemical_list: C505605:Fgf23 protein, rat; D010710:Phosphates; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D005346:Fibroblast Growth Factors; C496350:Fgfr1 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048049:Extracellular Signal-Regulated MAP Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins; C018279:sodium phosphate